tbuckley/cabot-search huggingface dataset:
The influence of treatment sequence in the prognostic value of <i>TMPRSS2-ERG</i> as a biomarker of taxane resistance in castration-resistant prostate cancer.
Authors: Òscar Reig, Mercedes Marin, Maria Mila, Albert Font, Montserrat Domenech, Alejo Rodriguez Vida, Joan Carles, Cristina Suárez, Aranzazu Gonzalez del Alba, Natalia Jiménez, Iván Victoria, Nuria Sala, Maria Jose Ribal, Sandra López, Olatz Etxaniz, Pablo Maroto, Pedro L. Fernandez, Aleix Prat, Begona Mellado
Journal: Journal of Clinical Oncology (2019)

235 Background: TMPRSS2-ERG expression at peripheral blood has been correlated with lower docetaxel benefit. This multicenter study prospectively assessed the role of TMPRSS2-ERG mRNA as a taxane-resistance biomarker in blood and retrospectively in tumors, and explored the impact of prior abiraterone/enzalutamide (A/E) in castration-resistant prostate cancer (CRPC) patients and in vitro. Methods: TMPRSS2-ERG was tested by quantitative reverse-transcription PCR. We included 204 patients (137 blood and 124 tumor samples) treated with taxanes. TMPRSS2-ERG expression was correlated with PSA-progression-free survival (PFS), radiological-PFS (RX-PFS), and overall survival (OS). Independent association with survival was evaluated by multivariate Cox modeling. ERG knockdown, combinatorial and sequential experiments with enzalutamide and docetaxel were performed in VCaP cells. Results: In the multivariate analysis prior A/E (HR: 1.833; P = 0.005) and blood TMPRSS2-ERG (HR: 2, 95%CI; 1.1-3.67; P = 0.018) , were independently associated to lower PSA-PFS. In patients without prior A/E, both blood and tumor TMPRSS2-ERG independently predicted lower PSA-PFS (HR 2.92; P = 0.014 and HR 1.82; P = 0.045, respectively) to taxanes. This was not observed in patients with prior A/E. There was a significant interaction between blood TMPRSS2-ERG detection and prior A/E related to PSA-PFS (P = 0.032) and RX-PFS (P = 0.009). In vitro stable ERG inhibition did not sensitize VCaP cells to docetaxel. Concomitant enzalutamide and taxanes were synergistic, but prior enzalutamide reduced docetaxel cytotoxicity in VCaP cells. Enzalutamide induced neuroendocrine markers and reduced E-cadherin expression. Conclusions: Prior hormone-therapy may influence taxanes response and TMPRSS2-ERG prognostic value. Thus, multiple and sequential biomarkers are needed in CRPC follow-up evaluation.
Applications of iron nanoparticles for thermochemotherapy of the experimental tumors.
Authors: Irina Aleksandrovna Goroshinskaya, Polina Sergeevna Kachesova, Pavel Viktorovich Svetickij, Andrey Pavlovich Svetickij
Journal: Journal of Clinical Oncology (2015)

e13519 Background: It is known, that in advanced and recurrent tumors processes of fibrosis, sclerosis and necrosis take place, and they reduce tumors’ chemoradiation and temperature sensitivity. The efficacy of the thermochemotherapymay be improved by increasing the sensitivity of cancer cells to these therapeutic factors. The purpose of this study was to investigate the possible use of metallic iron nanoparticles (FeNPs) measuring 30-75 nm as an agent for enhancing thermosensitivity of tumor tissue to improve the effect of treatment. Methods: The experiment was carried out on outbreed male rats weighing 220-250 g with transplantable tumors: sarcoma 45 (S45) and Pliss lymphosarcoma (LS). The experimental animals were divided into 2 groups: 1st group received paratumorally methotrexate (MT), after which was performed local UHF hyperthermia (to 42-43° C). In the 2nd group thermo-chemotherapy was combined with FeNPs administration. FeNPs were injected intratumorally 15 minutes before the hyperthermia session with MT. A total number of exposure: rats with S45 - 3 sessions, rats with LS - 5 sessions with an interval of 48 hrs. Control group consisted of tumor-bearing animals without any treatment. The antitumor effect of treatment was evaluated by the percentage of tumor growth inhibition (TGI %) and an index of efficiency (IE, mean tumor mass of the test group/mean tumor mass of the control group). Results: After beginning of the treatment in the test group of animals with S45 stabilization of the tumor growth, more pronounced in rats treated with FeNPs + MT were observed. On the day 7 after the 3rd exposure in the first group TGI was 28%, in the 2nd group TGI was 56.2%. IE values in the 1st groups amounted to 1.4, for the 2nd group – to 2.5. After 2nd exposure of the rats with SP in the group receiving FeNPs an expressed antitumor effect was observed (TGI - 76.4%). On the day 7 after the end of treatment in rats with the combination of hyperthermia +MT +FeNPs TGI was 86.8% and IE was 7.2. In the group of animals receiving hyperthermia+MT the values of TGI and IE were 43.4 % and 1.8 respectively. Conclusions: The data showed the potential applicability of metallic FeNPs as a thermo-sensitizer to enhance antitumor effect of thermochemotherapy with methotrexate.
<i>MYC</i> Drives Group 3 Medulloblastoma through Transformation of Sox2+ Astrocyte Progenitor Cells
Authors: Ran Tao, Najiba Murad, Zhenhua Xu, Peng Zhang, Konstantin Okonechnikov, Marcel Kool, Samuel Rivero-Hinojosa, Christopher Lazarski, Pan Zheng, Yang Liu, Charles G. Eberhart, Brian R. Rood, Roger Packer, Yanxin Pei
Journal: Cancer Research (2019)

A subset of group 3 medulloblastoma frequently harbors amplification or overexpression of MYC lacking additional focal aberrations, yet it remains unclear whether MYC overexpression alone can induce tumorigenesis and which cells give rise to these tumors. Here, we showed that astrocyte progenitors in the early postnatal cerebellum were susceptible to transformation by MYC. The resulting tumors specifically resembled human group 3 medulloblastoma based on histology and gene-expression profiling. Gene-expression analysis of MYC-driven medulloblastoma cells revealed altered glucose metabolic pathways with marked overexpression of lactate dehydrogenase A (LDHA). LDHA abundance correlated positively with MYC expression and was associated with poor prognosis in human group 3 medulloblastoma. Inhibition of LDHA significantly reduced growth of both mouse and human MYC-driven tumors but had little effect on normal cerebellar cells or SHH-associated medulloblastoma. By generating a new mouse model, we demonstrated for the first time that astrocyte progenitors can be transformed by MYC and serve as the cells of origin for group 3 medulloblastoma. Moreover, we identified LDHA as a novel, specific therapeutic target for this devastating disease. SIGNIFICANCE: Insights from a new model identified LDHA as a novel target for group 3 medulloblastoma, paving the way for the development of effective therapies against this disease.
Cytomegalovirus promotes murine glioblastoma growth via pericyte recruitment and angiogenesis
Authors: Harald Krenzlin, Prajna Behera, Viola Lorenz, Carmela Passaro, Mykola Zdioruk, Michal O. Nowicki, Korneel Grauwet, Hong Zhang, Magdalena Skubal, Hirotaka Ito, Rachel Zane, Michael Gutknecht, Marion B. Griessl, Franz Ricklefs, Lai Ding, Sharon Peled, Arun Rooj, C. David James, Charles S. Cobbs, Charles H. Cook, E. Antonio Chiocca, Sean E. Lawler
Journal: Journal of Clinical Investigation (2019)

Cytomegalovirus (CMV) has been implicated in glioblastoma (GBM); however, a mechanistic connection in vivo has not been established. The purpose of this study is to characterize the effects of murine CMV (MCMV) on GBM growth in murine models. Syngeneic GBM models were established in mice perinatally infected with MCMV. We found that tumor growth was markedly enhanced in MCMV+ mice, with a significant reduction in overall survival compared with that of controls (P < 0.001). We observed increased angiogenesis and tumor blood flow in MCMV+ mice. MCMV reactivation was observed in intratumoral perivascular pericytes and tumor cells in mouse and human GBM specimens, and pericyte coverage of tumor vasculature was strikingly augmented in MCMV+ mice. We identified PDGF-D as a CMV-induced factor essential for pericyte recruitment, angiogenesis, and tumor growth. The antiviral drug cidofovir improved survival in MCMV+ mice, inhibiting MCMV reactivation, PDGF-D expression, pericyte recruitment, and tumor angiogenesis. These data show that MCMV potentiates GBM growth in vivo by increased pericyte recruitment and angiogenesis due to alterations in the secretome of CMV-infected cells. Our model provides evidence for a role of CMV in GBM growth and supports the application of antiviral approaches for GBM therapy.
A phase III, randomized, open-label, multicenter, global study of durvalumab and bacillus calmette-guérin (BCG) versus BCG alone in high-risk, BCG-naïve non-muscle-invasive bladder cancer (NMIBC) patients (POTOMAC).
Authors: Maria De Santis, Ramil Abdrashitov, Axel Hegele, Margaret Kolb, Suzanne Parker, Juan Palou Redorta, Hiroyuki Nishiyama, Feng Xiao, Ashok Kumar Gupta, Neal D. Shore
Journal: Journal of Clinical Oncology (2019)

TPS500 Background: Standard of care (SoC) for high-risk NMIBC patients is transurethral resection of the bladder tumor followed by BCG. Although several randomized clinical studies have demonstrated the efficacy of BCG in NMIBC, recurrence rates are as high as 50% in the first 3 yrs of follow up and can be even higher for aggressive histologic subtypes. Immunotherapy agents active in the programmed cell death (PD) pathway responsible for suppressing anti-tumor immunity present an emerging treatment opportunity. In trials treating patients with metastatic urothelial cancer who progressed after platinum-based chemotherapy, response rates doubling those with traditional chemotherapy have been reported for immunotherapies targeting programmed cell death-1 (PD-1) and programmed cell death ligand-1 (PD-L1). Durvalumab is a selective, high affinity, engineered human IgG1 mAb that blocks PD-L1 binding to PD-1 and CD80 with a manageable safety and tolerability profile. PD-L1 inhibition with durvalumab in combination with other immunotherapies, including SoC BCG, may improve response rate and duration of tumor response. Methods: POTOMAC is an open-label, multicenter, global Phase 3 trial enrolling approximately 1,300 patients ≥18 yrs with histologically confirmed high-risk NMIBC who have undergone complete resection of papillary tumors (patients with residual carcinoma in situ [CIS] are eligible) and are BCG-naïve. Of those, approximately 975 patients will be randomized (1:1:1) to durvalumab (1500 mg every 4 wks for 13 cycles) + BCG induction (6x every 1 wk instillation) and 2 yrs of maintenance (3 doses x every 1 wk at 3, 6, 12, 18, and 24 months), durvalumab + BCG (induction only) or BCG (induction and 2 yrs of maintenance). Randomization will be stratified by high-risk papillary disease (Y/N) and CIS (Y/N). The primary endpoint is disease-free survival. Secondary endpoints include proportion of patients alive and disease free at 24 months, overall survival at 5 yrs, pharmacokinetics, immunogenicity, safety and tolerability, and HRQoL. Clinical trial information: NCT03528694.
Continuous infusion 5-fluorouracil (5FU) as a novel treatment for heavily pretreated prostate cancer patients: An update.
Authors: Charlotte Manogue, Patrick Cotogno, Marcus Marie Moses, Pedro C. Barata, Jodi Lyn Layton, A. Oliver Sartor, Brian E. Lewis
Journal: Journal of Clinical Oncology (2019)

319 Background: Currently patients failing multiple conventional therapies enroll on clinical trials but in many cases, despite a good performance status, patients may not qualify for trial enrollment. CRPC tumor cells typically express prostate specific membrane antigen (PSMA), a folate hydrolase which increases cell folate uptake (Yao et al. Prostate 70:305, 2010). We hypothesize that 5FU, functioning as an anti-folate, antagonizes the downstream effects of PSMA over-expression. Herein we present an update to our 5FU experience in heavily pretreated mCRPC. Methods: Data was retrospectively collected at Tulane Cancer Center for patient treatment history, disease history, performance status and laboratory parameters. All patients were treated with continuous infusion of 5-fluorouracil at a dose of 200mg/m 2 -day. Results: 24 patients at Tulane Cancer Center were treated with 5FU between Oct/2013 and Oct/2018. The median age was 72, patients had an median of 6 lines of prior therapy, and 37.5% had liver metastatic disease. The 30% and 50% PSA response rates were 41.6% and 29% respectively. Of the PSA responders, 100% had some level of PSA decline after 7 days of therapy with a median time to best PSA response of 2.6 months (95% CI 0.2-5.1). Median time on treatment was 11 weeks for the entire cohort and 18.5 weeks for patients with a ≥30% PSA decline; 20.8% of patients remained progression free by PSA at 4 months. Improvement in performance status as well as transfusion independence were noted in a subset of patients with myelophthistic anemia due to prostate cancer. No grade &gt; 3 AEs were attributable to 5FU. Conclusions: 5FU is a relatively inexpensive and well tolerated therapy that shows benefit in some heavily pretreated patients. Additionally, the ability to quickly assess the potential for response, and lack of &gt; grade 3 adverse events makes it a reasonable option for this population.
A retrospective study of the association between durations of fluoropyrimidine-based adjuvant chemotherapy and survivals in stage II or III gastric cancer.
Authors: Seong-Geun Kim
Journal: Journal of Clinical Oncology (2015)

e15088 Background: This study was conducted to propose the optimal duration of fluoropyrimidine-based adjuvant chemotherapy, which was consisted of fluoropyrimidine derivatives alone or fluoropyrimidine combined with intravenous platinum in stage II or III gastric cancer (GC). Methods: We retrospectively analyzed data from 2,219 patients with histologically confirmed GC who underwent curative gastrectomy with D2 lymphadenectomy between 2005 and 2012. 617 patients of stage II or III GC were analyzable. 187 patients (30.3%) were treated with surgery alone. 430 patients (69.7%) were treated with postoperative adjuvant chemotherapy. The duration of adjuvant chemotherapy less than 6 months [Group 1] was 147 patients (34.2%), from 6 months to less than 12 months [Group 2] was 94 patients (21.9%), from 1 year to less than 2 years [Group 3] was 139 patients (32.3%) and over 2 years [Group 4] was 50 patients (11.6%). Results: 5-year overall survival (OS) and 3-year relapse free survival (RFS) were analyzed according to durations of fluoropyrimidine-based adjuvant chemotherapy. Each 5-year OS in Group 1, 2, 3, and 4 was 75.7%, 87%, 90.3% and 93.4%. Each 3 year RFS in Group 1, 2, 3 and 4 was 52.5%, 58.8%, 81.4% and 94.0%. The longer period of adjuvant chemotherapy groups in stage II or III GCs obtained much higher OS and RFS. Conclusions: We suggest that a prospective cohort study should be performed to figure out whether the longer period of fluoropyrimidine-based adjuvant chemotherapy in GC could obtain much higher OS and RFS.
Oesophagus posters 442-464
Authors: S Parry, J Barton, M Welfare, I Mohammed, L Cherkas, S Riley, T Spector, N Trudgill, S Lal, J Mclaughlin, G Giampaolo, G Dockray, A Varro, D Thompson, J Jones, D Kendall, P Millns, C Hawkey, S Dunlop, D Jenkins, R Spiller, L Gregory, L Yaguez, S Coen, E Amaro, S Smale, A Hobson, S Williams, Q Aziz, V Chudleigh, E Brennan, S Tarry, S Myers, S Lewis, G Smith, K Palmer, Z Khan, E Simpson, A Cole, I Macdonald, D Pye, A Austin, J Freeman
Journal: Gut (2002)

Introduction: Previous studies, many uncontrolled, suggest 4 to 32% of people develop irritable bowel syndrome (IBS) after ID.Little information is available on the development of other FGIDs after ID.Aim: To determine if patients with stool culture confirmed bacterial diarrhoea were more likely to develop gut symptoms consistent with a diagnosis of IBS, functional dyspepsia or functional diarrhoea at 3 and 6 month follow up compared with community controls.Methods: A prospective community-based case-control study over one year.Subjects with stool positive bacterial infectious diarrhoea and control subjects from the same primary care practice were invited to participate.The presence or not of IBS, functional dyspepsia or functional diarrhoea was diagnosed at the start and at follow up using self-complete Rome II modular questionnaires.The diagnosis of a baseline FGID excluded subjects from continuing.There were 128 cases and 219 community controls eligible and who consented to participate.Results: At follow up there was a higher incidence of FGIDs in the cases compared with controls, mainly due to a higher incidence of IBS (see table ).There was no difference in the incidence of functional dyspepsia between cases and controls.Conclusions: IBS and functional diarrhoea is diagnosed more frequently in people at three and six-month follow up after an episode of stool positive bacterial diarrhoea compared with community controls despite careful exclusion of people with pre-existing FGIDS and adds further support for the concept of post-infectious IBS.
Abstract P259: Associations of Prior Head Injury With Physical Functioning
Authors: Andrea L Schneider, Dan Wang, Rebecca F Gottesman, Elizabeth Selvin
Journal: Circulation (2019)

Introduction: Head injury is associated with significant morbidity and mortality. However, associations of prior head injury with current physical functioning are less clear. Hypothesis: We hypothesized that persons with prior head injury would have greater impairment in physical functioning, particularly with functions requiring more complex thinking and organizational skills (e.g., managing money), compared to persons without head injury. Methods: We performed cross-sectional analyses of 6,293 participants in the 2011-2014 National Health and Nutrition Examination Surveys (NHANES), a nationally representative sample of noninstitutionalized civilian U.S. adults aged 2 40 years. Prior head injury was self-reported by the question, “Have you ever had loss of consciousness because of a head injury?” Measures of physical functioning were assessed by standard questions. We used logistic regression models to estimate associations and all analyses incorporated survey weights to account for the NHANES sampling design. Results: Overall, participants were a mean age of 57 years, 52% were women, 9% were black, and 15.3% had a history of head injury. Persons with a prior head injury were more likely to have limitations in any activity due to a physical, mental, or emotional problem (OR 1.88, 95% CI 1.54-2.29; Table ). Persons with a history of head injury were more likely to have difficulty walking up ten steps (OR 1.58, 95% CI 1.07-2.34), walking between rooms on the same floor (OR 2.68, 95% CI 1.02-7.03), performing household chores (OR 1.54, 95% CI 1.02-2.33), dressing (OR 1.75, 95% CI 1.17-2.62), managing money (OR 2.20, 95% CI 1.38-3.51), or attending social events (OR 2.48, 95% CI 1.47-4.19). Conclusions: Prior head injury is a potent risk factor for disability and has a strong link to limitations in physical, mental, and emotional functioning. Prospective studies are needed to better characterize the temporality of these observed associations.
Multidrug-resistant bacterial carriage and related healthcare-associated infections in a pediatric intensive care unit: a 6-year prospective study
Authors: Michael Levy, Stéphane Bonacorsi, Jérôme Naudin, Marion Caseris, Eric Thebault, Patricia Mariani-Kurkdjian, Maryline Chomton, Julie Sommet, Stéphane Dauger, Catherine Doit
Journal: Intensive Care Medicine (2019)
Rectal cancer recurrence in relation to pathologic margin.
Authors: Brian MacLaughlin, Ravin Kumar
Journal: Journal of Clinical Oncology (2015)

e14645 Background: The therapeutic approach to rectal cancer has evolved with neoadjuvant treatment and surgical approach. We sought to evaluate oncologic outcomes for rectal cancer patients at a county hospital. Methods: A retrospective analysis on rectal adenocarcinoma patients who underwent surgical resection at a university affiliated county hospital from 2006-early 2014. Patient demographics, chemoradiation therapy and surgical treatment, and pathologic review of surgical specimens were assessed. For patients with > 1 year follow up, time to disease recurrence was assessed. Analysis was performed with Student’s t-test and chi-square. Results: 134 patients with rectal cancer were identified, of whom 109 (81.3%) underwent surgery for curative intent. Ten (9%) had required prior diversion procedures and 9 (8%) required colonic stent placement prior to neoadjuvant treatment. At time of surgery, 8 (7.3%) were found to be unresectable and 5 (4.6%) had non-R0 resections. Of the 96 who underwent intended R0 resection, the average age was 54 years and 66% were male. One year follow-up is available for 63 (65.6%), with an average follow up of 33 months [range 1yr-7.4yrs]. The remainder are either within one year of surgery (26) or lost to follow-up (8). Twelve patients suffered recurrence at an average 29 months [range 4.2-83.6 months]. Local recurrence occurred most often (pelvic 4, anastamosis 3) with carcinomatosis in 2 and additional metastasis noted to liver (2), lung (1), brain (1) and spine (1). Complete pathologic response was noted in 7 patients (11%), none of which had recurrence. Thirty six (57%) of specimens had pathologic assessment of circumferential radial margin. Recurrent patients had closer negative circumferential radial margin than those without recurrence (0.7mm vs 8mm, p = 0.04) and a positive margin on pathologic specimen evaluation (57% vs 14%, p= 0.01). Conclusions: Among rectal cancer patients treated at a county teaching hospital, 18.7% were unresectable at initial evaluation. An additional 17% required surgical diversion or stent placement prior to neoadjuvant treatment. Among intended R0 resection patients, positive margin and close negative margin < 1mm were correlated with rectal cancer recurrence on average at 2.4 years.
Cytotoxic effects of cabazitaxel on human gliomaspheres and monolayer glioma cells: A comparative study between 2D and 3D cell cultures.
Authors: Atike Pinar, Ozge Ozer, Burcak Karaca, Emir Bozkurt, Ruchan Uslu
Journal: Journal of Clinical Oncology (2015)

e13049 Background: Three-dimensional (3D) in vitro modelling studies are of importance because conformation is crucial for cell-cell interactions in carcinogenesis. Cabazitaxel is shown to have transmission capability from blood-brain barrier and it is more potent than other Taxanes. In this study, we compared Cabazitaxel’s cytotoxic effects on GBM cell lines T98G and U-87 MG with 2D and 3D in vitro cell culture models. Methods: GBM cell lines T98G and U-87 MG were cultured as two-dimensional (2D) monolayer cell culture and 3D gliomaspheres by using hanging drop technique. Monolayer cells and gliomaspheres were treated with increasing concentrations (10-4-10-8 M) of Cabazitaxel for 24, 48, 72 and 96 hours. Cell proliferation was assessed by XTT assay and IC50 values were calculated by Calcusyn 2.1 software. Statistical data were analyzed by GraphPad Prism 6. Results: It follows from the cytotoxicity data that IC50 values of Cabazitaxel for gliomaspheres were higher than for monolayer cells. These differences may result from microenvironmental changes and cellular organization due to 3D spheroidal formation. Moreover, cellular organization of gliomaspheres might cause to decrease or slow penetration of the drug. While IC50 values for monolayer cells and gliomaspheres of T98G were 1 μM for 48h and 1.481 μM for 72h, IC50 values for monolayer cells and gliomaspheres of U-87 MG were 9.825 μM and 215.5 μM for 72h, respectively. Conclusions: This study might lead us for better understanding preclinical studies of GBM by using 3D cell culture model. Moreover, these preliminary results indicate that Cabazitaxel might be promising for the treatment of GBM.